DR. HANIF AHMAD

5. DR. HANIF AHMAD TMO Medical B Unit LRH

6. Case History • 18 yrs old un-married,male patient • sanitory worker • from Lahori gate Peshawar , • Admitted to Dermatology unit LRH through casualty on 31st January 2008 • Shifted to Medical B on 2nd Feb.

7. Presenting complaints High grade fever & headache 10 -12 days Nausea,vomiting & diarrhea Generalised body aches and pains with burning and pricking sensation of extremities Rash on the trunk & extremities Difficulty in walking

8. HOPI • He developed abrupt onset high grade intermittent fever with sweating,dry cough,nausea,vomiting & watery diarrhea. • Headache, chest and abdominal pain, arthralgias, myalgias,easy fatiguability. • Restricted ADL • Diffuse rash initially on the trunk,then spreading to etremities • Painful extremities with burning and pricking sensation with color changes (blackening) after a week . • Conjunctival injection • On/off history of oral ulcers, dysphagia.

9. No history of • Neurological symptoms • Urinary symptoms • Alopecia, photosensitivity, dry itchy eyes,pruritis,or joint swelling • Bleeding stigmata • Palpitations,dizziness,syncopy,or vertigo • Weight loss

10. Past Hx: Appendicectomy 03 months ago No other premorbidities • DRUG Hx:Not significant (no hx of using complementary or alternative medicine) • FAMILY HISTORY: • Father is sanitory worker by profession • They Live in a rented house of three rooms in crowded,unsanitory conditions. • Has one married elder brother living in the same house. • sister died at the age of 12yrs because of pulm TB. • No significant illness in the family.

11. SOCIO-ECONOMIC Hx: Not satisfactory • PERSONAL Hx: • Student of 8th class • Disturbed sleep and appetite during the illness,otherwise was normal • No hx of any substance abuse. • No hx of sexual,or animal contact.

12. Clinical Examination • Febrile,normotensive,conscious & well oriented;pulse=90/min(regular,non-collapsing); R.R=20/min with no cyanosis or resp distress. • Mildly pale,but not icteric. • Conjunctival injection was present • ENT examination was unremarkable except congested throat. • Diffuse red maculopappular rash with rain drops like hypopigmentation & scarring involving the trunk & extremities • Gangrenous changes in left toes & bilateral finger tips with intact peripheral pulses. • No nail changes or lymphadenopathy;no edema.

13. CNS,CVS,RESP, & GIT examination was unremarkable • No joint deformities or swelling • No evidence of proximal muscle weakness • No gait disorder or spine deformity • No genital ulcers,but poor personal hygiene.

14. On the basis of: Rash and digital gngrenes, the possibility of VASCULITIS,possibly due to MCTD was raised. However a possibility of Idiopathic Vasculitis OR Cryoglobulinemia was kept in mind. Was put on Steroids & Nifedipine emperically in dermatology unit. However he failed to show any improvement. Rather his digital gangrene started to aggravate. A call was sent to us and we, in consultation with dermatology VP, transferred him to MMB.

15. LAB STUDIES • Hb=8.9,with otherwise normal CBC • ESR=30 mm in 1st hr. • Normal LFTs,RFTs,S/E,RBS,Urine R/E,CXR,USG abdomen & pelvis,ECG,ECHO,PT,APTT & INR, • Normal Doppler U/S of upper & lower limbs • ANA: Negative RA-factor: Negative

16. TREATMENT • Steroid therapy was stepped up (Methylprednisolone pulse therapy was considered) and full supportive therapy was also instituted. • Heparin was started in full therapeutic doses, but his condition kept on deteriorating. • Methotrexate, cyclophosphamide,azathioprine, & prednisone are the recommended treatment options for vasculitis. • Cyclophosphamide is the drug of choice in this setting. However as oral form is not available and IV access was a problem with failed canulae sites so oral Azathioprine was started but to no avail. • At this time iv cyclophosphamide was considered to be the only and most potent option left with us. A CV-line was passed and was given two pulses of intravenous cyclophosphamide,but again we were disappointed as we saw this young boy slipping away from our hands day by day.

17. Serendipity • At this time one of our colleagues Dr S.Iqbal shah, while going through a color atlas of medicine came across this picture: • The picture belonged to a patient suffering from Typhus. • This clicked his mind because that picture had a lot of resemblance to our patient’s lesions;

20. The Real Diagnosis • After that the possibility of vasculitis secondary to TYPHUS rather than idiopathic vasculitis was strongly considered in our patient. • We went back to patient’s history and we could extract quite a few relevant points e.g: • patient’s personal hygiene has been poor. • some relatives had visited them from Lahore who, reportedly, were lice-infested.

21. Sigh of relief • We sent his blood sample immediately to AKUH lab for Typhus serology and put him on anti-typhus tretment i.e: Doxycycline. • To our surprise and satisfaction he showed dramatic response within 48hrs, with marked symptomatic improvement and mobilisation within a couple of days. • Cytotoxic drugs were stopped & steroids are being tapered off and the patient is in full spirits.

22. Final diagnosis LOUSE BORNE TYPHUS CAUSED BY Rickettsiae Prowazekii

23. Epidemic (louse-borne Typhus) • Epidemiology, Etiology and Pathogenesis • Louse-borne or epidemic typhus caused by R.prowazekii killed millions of people in eastern eureope and Russia during the periodic wars during the past two centuries. • Fortunately, epidemic typhus is now a rare disease however sporadic outbreaks still occure in parts of asia, russia, algeria and burndi and in the andes mountians of south america. • War, famine and human cruelty crowded un sanitory living conditions can result in epidemics. • Until 25 years ago, typhus was thought to involve in exculsive cycle b/w the body louse and infected humans. • However, a sylvatic cycle of infection with R prowazekii is now known to be endemic in the eastern united states. • This sylvatic cycle involves flying squirals and their ecto parasites. • A case report of epidemic typhus in a patient from the south western united states ( an area outside the known geographic range of the flying squiral) suggests the existance of aditional vectors or wild animals reserviors for R prowazekii. • The prinicipal vector for epidemic typhus is the human body louse (padiculus humanus corporis) althought occassinally the head louse (p humanis capitis) can also transmit infection. Both squiral flea and squira louse can also act as vectors for R-p in the sylvatic cycle of infection.

26. While taking a blood meal from humans, body lice defecate and regurgitate infective GI contents. • These highly infective substances are then inocculated into the skin where the person scratches the pruritic feeding site. • Lice feces remain infectious for as long as 100 days. • Dry infectious louse feaces may also enter the respiratory tract. • Thus human to human transmission of R-P can occur via the sharing of clothings or via transfer of infected lice feces from one human to another. • Transimissin of sylvatic form of epidemic typhus to humans occurs only when humans have direct contact with infected squirals or when squirals nesting in the attics of homes or removed or killed, leaving the lice that infested their nets to seek an alternative (human host). • Patients are infectious for the lice during the febrile period and perhaps two to three days after the fever returns to normal. • Infected lice pass R-P in their feces within 2 to 6 days of their blood meal can be infectious earlier if crushed.

27. Pathophysiology • After entering the human body R-P spreads via the blood stream and lymphatics to produce a generalized vasculitis. • The precise mechanism by which R-P produces cellular injury is poorly understood. • But the net effect of this infection is wide spread endothelial injury along with activation of humoral immune response, inflammation and coagulation. • This vasculitis may produce diffuse myocarditis, along with macroscopic and microscopic damage to msls and neural tissue, the spleen, kidneys and other internal organs (like interstitial pneumonia).

28. CNS involvement may result in so called typhus nodules, which comprise peri vascular infiltrates consisting of lymphocytes, macrophages and plasma cells.

29. Diagnosis • Clinical menifestations: • R-P infection produces two distinct clinical syndromes. • The most common is an acute severe infection that occurs 7-10 days after exposur to infected lice and may result in death. • A second, recrudescent form called Brill-zinsser disease may occur from 1-5 decades after a primary infection (R-P servives in lymphoid tissue) • Patients with acute epidemic typhus infection typically become abruptly ill with fever, headache and myalgias. • Other no specific symptoms such as cough abd.pain, nausea and diarrhea are common. • Skin rash in patients with epidemic typhus classically beghins several days after the onset of symptoms as a red macular or macculpapular erruption on the trunk that then spreads to the extrimities.

30. Although the skin rash is classically described as sparing the palms and soles and face, exceptions to this rule occure. • In sever cases of epi typhus skin rash may become petechial. Rarely gangrene of the extrimities has been described. • Conjunctivitis, hearing loss (8th CN neuropathy), flushed face, rales at lung bases, often splenomegaly can occur. • In spontaneous recover improvemnet begins 13-16 days after onset with a rapid drop of fever. • In humans, the clinacal featurs of sylvatic form of typhus are similar to those of the epi Form. • In one series, however only half of the pts. With the sylvatic form of R-P had a skin rash. • Pts. With epi typhus often have neurologic symptoms that may range from mild confussion and drowsiness to coma, siezures and focal neurologic findings. • As in other rickettsial diseases, jaundice and myocarditis may occur in sever cases.

31. Recrudescent RP infection (brill-zinsser disease) is generaly a much milder illness than acute epi Typhus. • The onset of BZ disease is often abrupt with chills fever and headache. • Skin rash typically begins 4-6 days after the onset of symptoms and it is often scant or evanescent. • Because pts. With BZ disease are often elderly or have other chronic medical conditions, their symptoms (EG, confusion, dyspnoea and lethargy) may be in correctly attributed to pre existing or co existing cardiac, CVS or pulmonary disease.

32. Lab studies • Both forms of RP infections are best diagnosed by serologic testing. • The indirect immunoflourescent antibody (IFA) test and an immunoblot technique are reliable serologic methods. • A 4 fold rise in antibody titres 10-21 days after onset of symptoms is considered diagnostic in both forms of RP infection, although only an IgG antibody response is illicited in BZ disease. • Common accompanying lab findings in acute epidemic typhus include increase plasma transferase level and thrombocytopenia, protienuria and hematuria. • Pts. With sever involvement may have pulmonary infiltrates on CXR and other lab evidance of myocarditis.

33. Treatment • Tetracyclines and chloremphenicol are effective treatments for both actue and recrudescent RP infections but the drug of choice is Doxycycline. • In one study, 35 of 37 pts. With epi Typhus were cured with a single 200mg dose of Doxycycline however the 2 remaining pts. Had relapse 6 and 7 days after the initial response. • Patients with RP infection, charicteristically imporve within 48 hrs of anti-RK therapy. • Doxcycline 200mg/d for 4-10days and Chloremphenicol 50-100mg/kg/d in 4 divided doses for 4-10 days. • In severe cases, supportive care with vasopressors, IV fluids, Oxygen and even dialysis may be necessary.

34. Prevention • Because humans who have contacted with other lice infested humans can secondarily acquire lice even if they have good hygiene, all louse infested persons and workers in closed contact with such persons should use long acting topical insecticides such as melathione, lindane or permithrine. • Fabrics and clothing treated with permethrine remained toxic to lice even after 20 washings. • In epidemic settings the use of chloremphenicol or tetracycline for prophylaxis of RP infection is highly effective. • Even a single 200mg dose of doxycycline takes once weekly by travellers or health care workers in areas where epi typhus is present has been shown to protect against infection • Prophylaxis should be continued for one week after leaving epidemic area • In activated vaccines have been shown to confere protection against experimental RP infections • Such vaccines are not currently commersially available nor are they likely to become avialable inveiw of the affectiveness of both prophylactic antibiotics and other preventive mesures.

35. Prognosis • In the pre antibiotic era higher mortality from epi Typhus was associated with old age and male gender • With prompt institution of anti biotic therapy however mortality is now rare