Derrick writes:

Hi there! It’s Derrick yet again, and funny story about last episode. My last diagnosis came before I went over nematodes in my intro to parasitology class, and it was in the middle of lecture I realized how wrong I was haha. Face palmed pretty hard when I heard my last email read aloud.

Since it seems to be a tradition to go over the weather; this is coming to you from Miami Florida, currently a cloudy 75 Fahrenheit (about 24 Celsius), humid as a swamp since we just had a heavy bout of rain. Before I submit my own diagnosis, figured you’d all be interested in our future AI overlord’s diagnosis. Take it away, chat GPT…

Based on the patient’s travel history, symptoms and laboratory results, the most likely diagnosis is Plasmodium falciparum malaria. The patient’s travel to India, Papua New Guinea and Thailand puts him at risk of acquiring malaria. The daily fever up to 40 C and the rash and cough suggests a systemic infection. The presence of three cropped vesicles on the penis could indicate genital herpes, which can be sexually transmitted, and the healed insect bite could be a red herring. However, the lower platelet count suggests a parasitic infection, which is common in malaria. Therefore, the most likely parasite afflicting this patient is Plasmodium falciparum.

When I further prompted it to list possible tests…

Additional tests that may be considered based on the results of initial tests or clinical suspicion include: blood cultures, urine cultures, serology for typhoid fever, scrub typhus, and other bacterial and viral infections. A skin biopsy of the vesicles on the penis may also be considered to evaluate for viral or bacterial infection.

Look out pathologists, AI is gunning for your careers. 

I’ll keep my own diagnosis brief. Symptoms include fever, itchy rash, three cropped penis vesicles and unproductive cough. Symptoms started three weeks after possible exposure.

Epidemiologically we have traveled from New Guinea to Thailand to Israel. Possible vectors; insects and contaminated water, not to mention soil. I’m going to disagree with the AI, as it seems our patient was taking anti-malarial drugs for most of his travels. An unproductive cough stands out to me, suggests a parasite that undergoes lung migration, and the delayed onset of symptoms also suggests the possible maturation of a nematode within our unfortunate host (molts?). Insect bites also stand out to me, especially the one that seems to take a while to heal. A possible infectious site? An itchy rash would suggest the parasite targets the subcutaneous skin layer, or bacterial/viral infection after a dirty worm entered our patient. 

After visiting my notes, my initial thought to most likely culprits based off of symptoms are Strongyloides fuelleborni, Ancylostoma duodenale (Hookworm), or Onchocerca volvulus. Strongyloidiasis seems likely, given that our patient was swimming in rivers it’s likely he took off his shoes and gave microfilaria a chance to penetrate his skin. Strongyloidiasis also seems to have a sporadic presence in New Guinea according to the CDC. I’m discounting Ancylostomiasis due to the normal blood count, and our last contender is Onchocerciasis. Now I’m gonna say due to probability, Onchocerciasis is more likely. Strongyloidiasis seems to have a “sporadic” presence, while O. volvolus has a stronger presence. Additionally the insect bite may be close to the penis, and those vesicles might be nodules formed around adult parasites that wandered the dermis to his penis (as a male, I can’t help but pity our patient if that’s the case). I agree with the AI, a skin biopsy of the penis vesicles would confirm or deny my suspicions. 

Eyal writes:

Hello, Vincent and all the sages of microscopic eukaryotes.

Greetings from Sydney Australia on the first day of daylight saving.

I apologise for this lengthy email in advance, but I do hope it would be entertaining and informative.

First, you guys made me laugh last episode discussing how to pronounce my name. Christina of course pronounced it perfectly but Daniel had the right idea of thinking as a Canadian when pronouncing it 🙂 After many years in the states, Europe and Australia I kept being surprised by how difficult it was for people to pronounce such a common Israeli name.

In Boston, I was eeeyal, where Australians are a lazy bunch and just go with eel. The best way I found is to basically pronounce it like “Hey, Al” but change it to Eh, Yal (not ee).

Second, I have used ChatGPT this week as I noticed it has come up multiple times over the last few months.

I thought I might explain some misconceptions about the technology. ChatGPT is basically just a statistic machine that takes a word and guesses the next word, and so on until statistically the next word is a ‘stop’. People refer to it as a Stochastic Parrot :). However, the way it ‘guesses’ the next word is where the magic of deep learning happens. 

The function that guesses the next word is a relatively simple algebraic function (ax+ay(cz+dw)…) but with a huge breadth (GPT currently uses 175 billion parameters (the example has 4 parameters) and the next version it’s in the trillions).

The model basically learned from all the text on the web to refine those parameters, and somehow the combination results in something that is pretty remarkable.

I had a discussion with ChatGPT on the case and this is what it looked like. (my guess is schistosomiasis with two courses of praziquantel one starting in 2 weeks (6 weeks post-exposure) and one 6 weeks later but it could also be malaria so treatment should start until ruled out).

Eyal: Let’s talk about only parasitic infections, are you happy with this?

GPT: Certainly! I am happy to discuss parasitic infections. Please let me know if you have any specific questions or topics you would like me to cover.

Eyal: I will give you a patient case and would like you to provide an analysis of which parasite might cause the symptoms, specifically in the context of the patient’s travel history. Please ignore any viral or bacterial options (note, I added this because, in a previous attempt, GPT included dengue fever which is a topic reserved for another podcast)

GPT: Sure, please provide me with the patient case and I will do my best to provide an analysis of which parasite may be causing their symptoms based on their travel history.

Eyal: This case is of a 24 year old male who presented to the emergency room at the end of February with a 4 day history of fever, starting three weeks after he returned from a long trip.

(Eyal reads the entire case to GPT)

He reports traveling in India during October of the past year. From November to early January, he stayed in Papua New Guinea, from where he traveled to Thailand, returning to Israel in early February. On admission he reports a daily fever up to 40 degrees C, which I think is 104 Fahrenheit. He also mentions an itchy rash and dry cough.

We learn a bit more about this patient. In Thailand, he received a five-day course of doxycycline due to a febrile illness, which resolved after treatment. During his stay in Papua New Guinea he hiked in the jungle, was bitten by multiple insects and also report finding leeches attached to his lower legs. One insect bite on his hip took a while to heal. He also reports swimming in multiple rivers. While travelling, he did not have unprotected sexual encounters but he admits to eating street food and home made food regularly. He received pre-travel vaccines and when he was in Papua New Guinea took Atovaquone Proguanil prophylaxis daily, discontinuing therapy a week after he flew to Thailand. On physical exam he is alert and oriented, vitals normal, the examination is unremarkable except for three cropped vesicles on his penis, which the patients says are itchy. A healed insect bite on his lower hip is also noted. His white blood count and differential are normal without eosinophilia. His haemoglobin is 13 g/dl, which is borderline normal and his platelet count is lower than normal with a count of 100,000 per microlitre of blood.

GPT: Based on the patient’s travel history and symptoms, one potential parasitic infection that could be causing these symptoms is a Plasmodium falciparum infection, which is the most deadly form of malaria. The patient’s travel history includes visits to areas of high malaria transmission, including India, Papua New Guinea, and Thailand. Additionally, the patient received doxycycline treatment in Thailand for a febrile illness, which could suggest a possible malaria infection.

Other possible parasitic infections that should be considered include:

Leishmaniasis: The patient’s travel history to Papua New Guinea, where he hiked in the jungle and was bitten by multiple insects, could suggest a possible leishmaniasis infection, which is caused by parasites transmitted by sand flies.

Schistosomiasis: The patient’s travel history also includes swimming in multiple rivers, which could suggest a possible schistosomiasis infection, which is caused by parasitic worms that live in freshwater snails.

Filariasis: The patient’s history of insect bites and finding leeches attached to his lower legs could suggest a possible filariasis infection, which is caused by parasitic worms transmitted by mosquitoes and other insects.

However, given the patient’s symptoms of fever, itchy rash, dry cough, and low platelet count, malaria seems to be the most likely parasitic infection, and it is important to confirm this diagnosis with laboratory tests such as a blood smear or a rapid diagnostic test for malaria. Further evaluation of the patient’s symptoms and laboratory findings may also be necessary to rule out other parasitic infections.

Eyal: Thanks for this assessment. Based on the patient not presenting with Leishmaniasis symptoms or any lymph node abnormalities, I think Leishmaniasis and Filariasis are not likely. what tests would you run to differentiate and confirm malaria, or Schistosomiasis? please don’t suggest a stool exam as there wasn’t enough time from potential infection for the worms to start generating eggs.

GPT: You are correct, given the patient’s symptoms and physical exam findings, Leishmaniasis and Filariasis are less likely than malaria and schistosomiasis.

To differentiate and confirm malaria, a blood smear or a rapid diagnostic test for malaria would be necessary. The blood smear is a microscopic examination of the patient’s blood to look for the presence of Plasmodium parasites. This test can differentiate between the four main species of Plasmodium that cause malaria and can also determine the severity of the infection.

To confirm a schistosomiasis infection, various diagnostic tests can be used depending on the stage of the disease. Since the patient has just returned from a trip, it is unlikely that schistosomiasis infection has progressed to the chronic stage, where eggs are excreted in feces or urine. In this case, the preferred diagnostic test would be a serological test such as an enzyme-linked immunosorbent assay (ELISA), which detects antibodies against the schistosome parasite in the patient’s blood. Another possible test is a urine-based test called the circulating cathodic antigen (CCA) test, which detects a protein produced by the schistosome parasite.

It is important to note that these diagnostic tests are not always conclusive, and additional tests or further evaluation may be necessary to confirm the diagnosis.

Eyal: considering the patient is in Israel. What treatment course would you recommend for both malaria and schistosomiasis?

GPT: The treatment for malaria depends on the severity of the infection, the species of the parasite causing the infection, and the patient’s medical history and age. For Plasmodium falciparum infection, which is the most deadly form of malaria, the treatment of choice is usually a combination of antimalarial medications, such as artemether-lumefantrine, atovaquone-proguanil, or quinine plus doxycycline or clindamycin. Given the patient’s travel history and symptoms, it would be reasonable to initiate treatment for malaria while waiting for the results of diagnostic tests. It is important to note that early treatment of malaria is crucial to prevent complications and further spread of the disease.

For schistosomiasis, the treatment of choice is praziquantel, which is a medication that kills the adult worms. The dose and duration of treatment depend on the species of schistosome and the severity of the infection. Since the patient has just returned from travel, it is important to consider the possibility of co-infection with other parasitic infections, which could require additional or different treatments. It is recommended that the patient receive medical evaluation and treatment by a healthcare professional with experience in tropical medicine and parasitic infections.

Eyal: You know, now that you mentioned the treatment options for malaria I remembered that the patient has received doxycycline in the recent past. Wouldn’t that decrease the likelihood of a malaria infection?

GPT: Yes, you are correct. Doxycycline is one of the medications used for malaria prophylaxis, which means it can prevent malaria infection in individuals traveling to high-risk areas. However, doxycycline is not 100% effective in preventing malaria, especially if the individual has not taken the medication as prescribed or has been exposed to malaria after stopping prophylaxis.

In the case of this patient, he has already completed a course of doxycycline for a febrile illness during his trip to Thailand, which suggests that he was likely taking the medication as prescribed. However, it is still possible that he could have been exposed to malaria during his travels, especially if he did not use mosquito repellent or bed nets consistently or if he visited areas with high malaria transmission rates.

Therefore, while the patient’s use of doxycycline for prophylaxis may decrease the likelihood of a malaria infection, it does not rule out the possibility entirely, and diagnostic tests for malaria should still be considered given his symptoms and travel history.

Eyal: That is so kind of you. Thank you. 

I find this very interesting and think that combined with a knowledgeable person, this kind of technology could be a huge power multiplier tool.

Side note: you should always be kind and respectful even if the other side is not carbon-based. You never know what the future holds 😉

Eyal

Stefan writes:

Dear TWIP team,

This is my first time trying to solve one of your riddles and I hope that despite the intense red herring exposure of the feverish patient from Israel I can make a reasonable educated guess!

In fever in a returned traveler many differential diagnoses need to be considered. This is even more true in this case of extensive travel history to many countries, in rural areas and for a prolonged period of time and with some very popular exposures like street food. Differentials can be limited by clinical presentation and incubation periods, some I exclude since after all this is TWIP : )

Viral causes: most tropical infections like dengue have a maximum 14d incubation period, which we can therefore rule out. In a patient with genital ulcers (which may cause us to ask some more questions about sexual exposures) we should also rule out Herpes (type 2) infection as well as syphilis and acute HIV-infection. Other STDs and partner testing is advised!

Bacterial causes to consider are typhoid fever (food exposure), leptospirosis and rickettsial infection (wildlife exposure). For typhoid I would culture blood, the others are clinical and serologically diagnosed, though scrub typhus has a too long incubation in this case (but may have been the cause of previous rash treated with doxycycline).

So we reach parasitic fever causes. The most relevant of course would be malaria. And interestingly, Papua New Guinea would have a high risk of falciparum malaria and the incubation period, especially after taking prophylaxis and suboptimal adherence or adsorption may be many months. Thrombocytopenia is a hallmark in malaria and is most commonly caused by malaria or dengue in returning travelers.

In our case however I vote against falciparum malaria since our patient has been on prophylaxis and likely was infected in Thailand. For most common tertiana/quartana malaria the fever pattern does not quite fit, so I have the suspicion that the TWIP team chose an exotic and still rather rare plasmodium species: P. knowlesii. This is endemic in jungle regions in Southeast Asia and has a sylvatic cycle among primates and is only zoonotically infects humans, especially where wildlife/human territory borders are breeched. In our case extensive jungle exposure without repellent would be the risk factor. Knowlesii malaria can be severe and does not have tertiana fever pattern, but rather daily fever as described in the case. To diagnose it I would do (repeated if negative) blood smear or a quantified buffer coat (QBC, if available).  Since morphological speciation may be challenging for P. knowlesii (looks similar to P. malariae) a confirmatory PCR may be considered. Rapid tests, of note, may not detect this species and should always be accompanied by direct smears. I would treat with oral artemisinin combination therapy if the patient is stable and able to ingest food, otherwise an intravenous therapy with artesunate is warranted (also in case the parasitemia is in the % range).

Closing, the rash may be unrelated (e.g. ancylostoma, strongyloides), skin manifestation in malaria are often petechiae and I would not expect those with this high a platelet count. The cough, if parasitic, might be lung migration by various agents, but normal eosinophiles speak against it. I would do a CXR to rule out concomitant bacterial infection. In a sick malaria patient there may be acute respiratory distress syndrome (ARDS) so proper fluid management is key in malaria treatment.

I hope this guess is correct but either way, I would be grateful if you could let me know how to pronounce “knowlesii” : )

Thanks for all your work, please keep it up,

Best wishes and happy Easter

Stefan from Heidelberg (sunny and 3°C), Germany

Hakon writes:

Hello from Athens,

This week’s case had me stumped- so many potential things the person could have and so many potential red herrings. Had to bring in the “big guns”. My mom was a navy physician in Thailand and the Philippines about 30 years ago and as such was used to seeing more exotic infections than are typically seen here in the states. Originally we were going to discount the phallic vesicles as some sort of herpes or other viral infection he had concurrent with myriad other potential infections. However, if it was to be assumed that it was also a symptom of the main parasitic infection then I would have to guess it to be a case of filariasis. Given the patient got better after a course of doxycycline (something we give in veterinary medicine prior to deworming in order to “shrink” the worms by killing their endosymbiotic bacteria Wolbachia) this was the best guess we could come up with. Biopsy of a vesicle as well as potentially screening for microfilaria as confirmation of one of these worms would confirm diagnosis. While treatment isn’t usually necessary for dirofilariasis it is clear here that we might use ivermectin and/or DEC (Diethylcarbamazine) should it turn out to be correct. Probably would not hurt to get a blood smear to confirm the patient doesn’t have babesia or plasmodia in them as well. 

All the best, 

Håkon  

Michelle and Alexander from the First Vienna Parasitology Passion Club write:

Dear Hosts,

The case of the young man returning from his travels in southeast asia presented a considerable challenge for us. Many parasitic pathogens fit some but not all symptoms, and worse, many are inconsistent with the findings. Even after consulting with significantly more experienced colleagues, we were unable to come to a diagnosis with a reasonable amount of certainty. Therefore, we will only discuss some diseases that we have considered and add a few thoughts regarding the problem representation.

Several aspects of the case are challenging: the symptoms of fever and cough are very non-specific, while the vesicular rash on the glans of the penis and the slow healing insect bite on the hip are typical only of a small number of entities. Considering pretest probability, the most likely explanation for the penile rash is genital herpes. The insect bite is typical for scrub typhus, which would be our number one diagnosis to consider in this patient, if this were not a parasitology podcast. The patient also received a 5 day course of doxycycline which is the correct treatment option for scrub typhus, also known as Tsutsugamushi fever. Nevertheless, 5 days could have been too short and there is also a possibility of doxycycline resistance. 

We chose to assume that both are artifacts, as the only parasitic infection to our knowledge that would cause a lesion like the one on the patient’s hip would be cutaneous leishmaniasis, which is not consistent with the patient’s other symptoms. We know of no parasitic infections that cause penile vesicles.

Several helminthic infections, including strongyloidiasis and other hookworm infections, trichinellosis, acute schistosomiasis and paragonimiasis fit the epidemiology and at least part of the symptoms, but are rendered highly unlikely by the lack of eosinophilia in the peripheral blood. 

While malaria is the most important differential in any traveler returning from an endemic region with fever, the correct use of prophylaxis and the incubation period of the disease make this seem unlikely. Still, infection with Plasmodium species, including P. falciparum and P. knowlesi, should be excluded. While rare, babesiosis might also be considered as a differential, as the efficacy of malaria prophylaxis against the disease, which is very rare in southeast asia, is doubtful.

Visceral leishmaniasis may cause a fever and generally lacks eosinophilia. The slow-healing ulcer is usually found in cutaneous, not visceral disease. Patients with VL usually have pronounced jaundice and hepatosplenomegaly, which is not described here. Trypanosomiasis seems impossible considering the epidemiology, as does african tick bite fever, which is also not a parasitic infection. 

Even after consulting our most experienced attending, we were unable to come up with a satisfying diagnosis. In a real world scenario, we would pursue further diagnostics and consider scrub typhus the most likely diagnosis. We can’t wait to hear what parasitic disease was troubling the young patient. 

Thank you for this great case. All the best, 

Michelle and Alexander from the First Vienna Parasitology Passion Club

Kimona writes:

Dear TWiP Team,

No slam-dunk! 

I began filtering for parasitemia w/ incubation period and fever onset >3 weeks post return from an extended SE Asia trip, with low-normal hemoglobin, mild thrombocytopenia, yet no eosinophilia. The latter excluded most helminthic causes, since eosinophilia is usually associated (trichinella, ascariasis, filariases, paragonimiasis). Schistosomiasis acquired during a river swim should also induce eosinophilia, as would visceral Leishmaniasis. The painful bite to his hip region sure sounded suspicious for some type of riduviid bug or Tse-Tse fly and possible trypanosomiasis, yet geographically his travels don’t fit. 

Ultimately, I kept returning to Malaria! 

P. falciparum and P. vivax are listed as the most abundant species in PNG and are also common in more rural areas of Thailand. Hypothetically, he could have been infected with P. vivax alone or as a dual infection with P. falciparum. The atovaquone-proguanil prophylaxis should help resist infection with even chloroquine-resistant forms of both these species, yet it would not prevent hypnozoite formation by P. vivax. We also know that one can develop malaria despite using chemoprophylaxis. He was later given doxycycline for a febrile illness once in Thailand. Doxy is listed as a slow acting schizontocidal agent, which could delay the first relapse to 5-7 weeks after finishing treatment. Alternatively, he could have a recrudescence from incomplete clearance of infection after his initial treatment with Doxy. Either of these may fit with the onset of fever 3 weeks after his return. One study found the risk of relapse for P. vivax following antimalarial treatment was 33% in returning Swedish travelers.

I haven’t been able to connect the penile vesicles with any obvious blood-sucking leech!! but instead postulate that this may be reactivation of a pre-existing genital herpes infection, possibly due to the stress of his malarial illness. There is also mention of increased rates of viral or bacterial infections while infected with malaria, which could explain his dry cough, as I am not sure this would be expected during a relapse (and not initial infection). 

Diagnosis would ideally be made by Giemsa-stained blood smear microscopy, allowing for species identification, quantification of parasitemia, and life cycle stage. RBCs infected with P. vivax are enlarged and often show stippling on the membrane, known as Schuffner’s dots. There are also rapid diagnostic tests which are convenient yet require a higher blood parasitemia load for detection. PCR can detect very low levels but is often limited to research settings.

Treatment with atovaquone-proguanil in SE Asia has cure rates >95%, but since he acquired his infection on this prophylaxis, a different therapy should be used. Artemisinin combination therapies, hydroxychloroquine, quinine plus doxycycline, tetracycline, or clindamycin – are all listed as options. And for antirelapse therapy he will require the additional treatment of hypnozoites with either primaquine or tafenoquine. 

The lack of significant anemia is what has caused me the greatest hesitation in choosing Malaria as my answer. Regardless, I learnt a lot in my readings!

In suspense……and always, in great appreciation!  Kimona

Christopher writes:

Hi Twip-sters, 

This case has had me writing differentials up on my whiteboard for about an hour now. As a good rule of thumb, any person who has traveled to a malaria endemic region who returns with recurring fevers has malaria until proven otherwise. My guess is an incipient P. falciparum infection as we see marginally low hemoglobin, thrombocytopenia, and daily fevers. P. falciparum infection is often described as tertian fever, which is a fever occurring every second day, however early in its infection, the protozoan may still have not adjusted its circadian rhythm. The associated stress of malaria infection may have caused an outbreak of Herpes simplex that could explain the lesions on the penis. I would say this is just hand-waving at this point, it’s a tough case! 

— 

Christopher Hernandez

David Geffen School of Medicine at UCLA, Medical Student 

MPH, Infectious Diseases and Vaccinology 

University of California, Berkeley

Kevin writes:

Hello TWiP team!

It is currently – albeit unpredictably – a sunny, but windy 61 F, 16 C in St. Louis where we are rounding second on Spring and baseball season is in full bloom!

My evaluation regarding the rambling gadabout with fevers, rash and cough is that this person is experiencing a recurrence of infection with a protozoa of the genus Plasmodium. (i.e., Malaria) 

There are a number of findings in this case which point to Malaria and a number which are misleading. First, his recent travel to multiple tropical countries with a relatively higher incidence of malaria (1-3) where he “was bitten by multiple insects” and presents with a recurring fever, months apart, indicate that this diagnosis should be high on any differential. That doxycycline resolved a previous illness, the thrombocytopenia (4) and the normal WBC & eosinophil count provide further support (5). HIV should always be a concern, but the H&E lessens this possibility I think. I believe the finding of his eating habits is misleading because I would expect other parasites to cause more intense symptoms, eosinophilia, or digestive issues in presentation (6-7). I also think the fly bite on his hip is deceptive – my first thought here is around leishmaniasis, but I would expect a different timeline or presentation with something like the cutaneous or visceral forms of this disease (8). Finally, the skin findings on his genitals are nonspecific and may or may not connect to this diagnosis (9).

There are two primary methods for diagnosing malaria based on my readings (4). The first is a classic, Giemsa-stained blood smear which I would order. This test can confirm a diagnosis, identify which species is responsible, and guage the severity of parasitemia. If the initial smear comes up negative, new specimens should be drawn every 6 hours if suspicion is high, though I do not know for how long.  The second method is a rapid, antibody-based test that does not require a microscopist, but can be poorly specific and sensitive for the species P. knowlesi. I am not sure which is preferable in practice. If confirmed, I would follow up with a PCR test to identify if the infection is drug-resistant (4). This step would be critical in determining the course of treatment. If there is a positive result, this would not be unexpected, as this patient has had a recurrence of infection after prophylaxis and drug-resistant species of P. falciparum and P. vivax have been well documented in forested regions of Southeast Asia (10).

Treatment selection is based on severity of presentation, species, and drug susceptibility (4). Severe malaria is treated with cinchona alkaloids or artemisinin derivatives, and can be treated with quinidine, but seems to require extensive monitoring and tracking of the patient. It is unclear that this patient has or is developing a “severe” form of the disease. For non-complicated malaria the treatment of choice depends on where the patient would have acquired the disease, but in this case, because chloroquine resistance is so prevalent, artemisinin combination therapy is preferred. 

Looking forward to more episodes!

Sincerely,

Kevin

References:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279679/

https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-019-7620-5

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04363-8

https://www.cdc.gov/dpdx/malaria/index.html

Parasitic Diseases, 7th Ed. (2019)

https://pubmed.ncbi.nlm.nih.gov/15831107/

https://www.cdc.gov/parasites/leishmaniasis/disease.html

https://ijdvl.com/cutaneous-findings-in-five-cases-of-malaria/

https://www.cdc.gov/malaria/malaria_worldwide/reduction/drug_resistance.html

Omar writes:

Salaam esteemed doctors,

We are in the midst of the holy month of ramadan and as you well know fasting is integral to our practice during this month, so you will forgive any lapses in my email, it is late in the evening as I type this email (so i suspect I’m a little hypoglycemic) and I am eagerly awaiting the time to break the fast.

I write to you from a sleepy coastal town in Tanzania called Bagamoyo, where we are bracing for the onset of the bi-annual rainy season called “Masika” and the cases of complicated malaria that it drags in with it.

I work in the clinical trial center of a research institution, I have a clinical background ,being a trained medical doctor (a relatively fresh one I should add). Here,we have and continue to conduct Phase 1 clinical trials on a number of malaria vaccines (pre-erythrocytic,blood stage and transmission blocking vaccines) including the RH5,R21,Pfs25 vaccines and a few others. Prof. Emeritus Despommier will be interested to hear we are trail -blazers in the field of malaria challenge studies in Africa.We conducted the first ever liver stage challenge in a malaria endemic country in Africa right here, back in 2016 and recently I was the primary clinician in the first blood stage malaria challenge in semi-immune African adults  that we only just completed(squeaky bum stuff).we are also evaluating vaccines against Rabies and Ebola that utilise an adeno-virus vector.

Onto the young man who presents with fever after venturing to Guinea and Thailand ,

I straight away suspected a case of Malaria (probably because it makes up roughly 40-60% of the cases I see around this time of the year) with P.vivax being the culprit and seeing as it is endemic in southeast Asia this further raises the suspicion.

Doxycycline is a capable schizontocidal and that is why it resulted in relief of his clinical symptoms after administration, but lest we forget p.vivax is notorious for its dormant hypnozoite stage in the liver and this must explain the relapse after returning to Israel owing to the weak gametocidal effect of the drug.

A thin blood smear would be ideal for identifying the species of plasmodium(this after a rapid test to diagnose malaria initially) ,the findings of mild thrombocytopenia and borderline haemoglobin value are also in keeping with a malaria diagnosis though I would have also expected to see mild lymphocytopenia as well.I suppose a PCR would also satisfy the purpose, but is overkill in this case (we routinely use this in our clinical trials though).

Treatment should be with an artemisinin based therapy,a three day course of artemether-lumefantrine should do the trick BUT the young man should also be prescribed a stat dose of primaquine as a gameticidal ,this should be given after establishing the patients G6PD status since the drug comes with the potential for hemolysis in deficient individuals,something that we practice with all trial participants in malaria challenge studies before we clear them of the infection .

That being said, I am in the process of finalizing a fellowship for the WHO-CRD TDR fellowship program, which I plan to undertake with Medicines for Malaria Venture (MMV) in Geneva, Switzerland and I do not know if any of the esteemed doctors have affiliations there, if so It would be a great opportunity for me to meet and be inspired. 

Please do give me a shout should any of you ever find yourselves in Tanzania in the future, plenty of beautiful national parks and I would be happy to show you around our research center and introduce you to all the exciting work we do, including with our entomology unit.

Yours humbly 

Omar

Daniel writes:

Hello everyone

My name is Daniel

I found the last case very interesting and challenging. Please keep them coming!

The 24 year old male presenting with an acute febrile illness and thrombocytopenia returning from his travels brings to mind a wide differential including: Malaria, Yellow Fever, Zika, Tick Bite Fever, Dengue, Chikungunya, meningococcal meningitis, Leptospirosis and viral hepatitis. 

The pruritic rash, dry cough and long incubation period of 3 weeks narrows the broad differential. Cutaneous larva migrans results in a serpiginous pruritic rash and can have an incubation period of over a month. Scabies can result in pruritic rash and can result in nodulo-papular lesions on the genitals. Trichinellosis can result in pruritic rash and cough after consumption of undercooked meat. Strongyloidiasis can cause cough and rash. Gnathostomiasis can cause pruritic skin lesions and fever 3-4 weeks after ingestion of raw or undercooked meat.

I found it difficult to tie in the penile vesicles. I think this could possibly be a red herring. Possibly this is reactivation of latent Herpes simplex due to immunosuppression from his acute illness.

Of the differentials I think Tick Bite Fever is less likely as he was treated with 5 days of Doxycycline for a febrile illness, possibly for TBF; as he had a lesion on his hip which was slow to heal, which could be an eschar. Tick bite fever also has an incubation period of 8 days while his illness presented 3 weeks after returning from Thailand.

Yellow Fever has an incubation of three to seven days; So this also does not fit. He is also likely to have been vaccinated for this prior to travel.

Dengue too has a short incubation period of 5-7 days.

Malaria knowlesi can have an incubation period up to 21 days and is endemic to Thailand so I would want to exclude this with a Malaria rapid test and thick and thin blood smears.

My guess is hookworm infection, in particular, Ancylostoma ceylanicum. Hookworms can cause papular-vesicular lesions at their point of entry, anemia and dermatitis as well as respiratory symptoms if the worm burden is high. Diagnosis would be by stool microscopy.

It is a wild stab in the dark. I am perplexed by this case.

Thank you for your intriguing cases

Kind regards

Daniel

James writes:

So in summary: 

24 y.o. male with fever and itchy rash, dry cough. Traveled to India, Papua New Guinea, Thailand, then Israel. Multiple insect bites. Swimming in rivers. Eating regular food. Took malaria prophylaxis in New Guinea but quit in Thailand. PE: vesicles on penis, itchy. WBC normal, minimally low end RBC and Plt’s. No eosinophilia. 

Hm. 

Protozoa? 

Daily fever x 4 days is a little weird for malaria but that is the least “zebra” of the protozoal possibilities. P. knowlesi can do daily fevers, comes from monkeys, and is endemic in SE asia, fits pretty well. Blood films look a lot like falciparum and a lot of medical folks don’t even KNOW about KNOWlesi. (I teach it to my DO medical students.) There is a PCR I believe. This is probably my favorite and leading Dx. (your cryptic comment about giving the most precise Dx fits this as well.) It can be a serious infection. Sometimes malaria can have petechiae and purpura or other rashes but this is less common. 

Other malaria’s are possible and maybe the fever hasn’t settled on its rhythm. Blood film, again, and maybe other molecular tests.  

Leishmania probably belongs on the list, skin symptoms a lot more common. Fever OK. Nasty hip bite is a decent History item as well. 

Trypanosomes seem unlikely. Luminal/GI protozoa is a stretch I think. 

Worms? 

No eosinophils is a soft negative here; when I was a fresh young naïve MD PhD at Duke I just equated eosinophils with parasites, but in my path residency learned “not so fast dude.” Drug reactions, allergies, there are even eosinophilic leukemias. Still and all tissue worms often have eos. 

I guess I’d consider schistosomes from swimming, various filarial nematodes from bites, etc. 

I still like knowlsei. I wonder if the vesicles are herpetic? Condoms are not nearly 100% effective for viral diseases. 

James M. Small, MD, PhD, FCAP

Professor of Pathology and Microbiology

Director of Clinical Career Advising

Rocky Vista University

Parker, CO